2.1 Nasopharyngeal Cancer
Nasopharyngeal cancer (NPC), although rare in North American, is the seventh and ninth leading cause of death for men and women, respectively, from Taiwan, southern China (in particular, Hong Kong and the province of Guangdong), and Southeast Asia. NPC comprises 18% to 25% of all cancers in these endemic areas while it represents only 0.2% of all malignancies in the United States (J. Cary, Moorhead, Md., 1994, “Nasopharyngeal cancer”). The most frequently suspected etiologic factors associated with the development of nasopharyngeal cancer are viral, genetic and environmental. Other risk factors include smoky surrounding, preserved food-rich diets such as salted and pickled fish, smoked meat, sausage or duck with high levels of salt, nitrite and/or N-nitrosamines, low intake of fresh vegetables and fruits, and cigarette smoking.
It is extremely difficult to diagnose NPC for several reasons. First, the symptoms are nonspecific at the early stages of the disease. Second, the tumor tends to spread submucosally and thus remains clinically unapparent even to direct inspection. Most importantly, the nasopharynx region is inaccessible to general examination and therefore, makes diagnosis difficult. The mean delay form the onset of the first symptom to diagnosis was reported to be six months (Skinner et al., 1990, Ear Nose Throat J. 69:237–252). Patients with NPC are most often present with a cervical mass from metastatic spread to a lymph node. Other possible presentations include ipsilateral serous otitis, hearing loss, nasal obstruction, frank epistaxis, purulent or bloody rhinorrhea, and facial neuropathy or facial nerve palsies.
A neck mass is consistently one of the most common presentations, and unfortunately, a sign of advanced disease. In fact, more than 50% of the patients when being detected of the cancer are in advance disease stages, and for this group of patients the 5 year survival figures are only around 50% after radiotherapy alone. Specifically, biopsy data reflects an extremely high rate of aberrant metastatic spread, which has been identified as the leading cause for death in NPC patients. Once the tumor begins to spread to the head and neck and to subcutaneous and cutaneous sites, the patients' average life span is down to about 4 months.
Studies show that 90% of nasopharyngeal cancer patients are infected with the Epstein-Barr virus (EBV), compared to less than 10% in the general public. Accordingly, Serologic markers for the Epstein-Barr virus (EBV) also plays a role in detection of the disease (Mutirangura, 2001, Ann NY Acad Sci. 945:59–67). DNA from EBV is found in nasopharyngeal tissues, and elevated titers of IgG and IgA antibodies are seen in all patients with nasopharyngeal cancer (Niedobitek et al., 1991, J Path. 165:17–24). Elevated titers have been used as a marker to screen populations in high-risk areas and as an indicator of the likelihood for relapse.
Using the World Health Organization classification system, NPC is histologically subclassified into types 1, 2 and 3. Under this scheme, type 1 carcinoma is the most differentiated and is also known as keratinizing squamous cell carcinoma, accounting for 25% of all NPC. Type 2 NPC, also referred to as non-keratinizing, is the least common, representing only 12% of NPC. WHO type 3 is also called undifferentiated carcinoma and accounts for 63% of NPC. Despite their histologic appearance, all of these tumors have been demonstrated by electron microscopy to be varieties of squamous cell carcinoma.
The staging of NPC is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
Radiotherapy is the mainstay of therapy for NPC due both to the inaccessibility of the tumor to surgery, and also to the surprising radiosensitivity of the lesion. However, the close proximity of the tumor to many vital structures makes NPC one of the most challenging tumors for the radiotherapist to treat. Although a wide variety of protocols is used, a standard recommended treatment regimen is 6500 to 7000 cGy delivered to the tumor by a linear accelerator by one anterior and two laterally opposed fields. Shielding of the eyes, tongue, brainstem, and spinal cord is essential. Small cancers of the nasopharynx are highly curable by radiation therapy, with survival rates of 80% to 90% (Ho, 1996, Int J Radiat Oncol Biol Phys. 35(3):463–469).
Surgery plays only a supportive role in the treatment of NPC because it is limited by the inaccessibility of the lesion and the difficulty in achieving resection of the tumor with clear margins in the face of the convoluted nasopharyngeal anatomy. In refractory cases, reirradiation techniques such as arc radiation or intracavitary implants would generally be considered preferable to surgery. Surgery for cervical lymphadenopathy is usually reserved for salvage following radiation therapy.
On the other hand, chemotherapy may be used as an adjunct to radiation therapy. The addition of chemotherapy may decrease the possibility of distant metastatic spread by eradicating micrometastases. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting and diarrhea. Active chemotherapeutic agents include cyclosporin A, Taxol, Cisplatin, Carboplatin, Adriamycin, Doxil, Topotecan, Methotrexate, Bleomycin and Epirubicin.
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkinson, 2001, Lung Cancer 32(3):265–279; Hoffman R M., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp 37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3):193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents and radiation are useful in the treatment of nasopharyngeal cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.